Development of Neurotensin-based Analgesics

项目摘要/摘要：慢性神经性疼痛是美国最重要的未满足的医疗需求之一，影响着全国数千万至数亿人在他们一生中的某个时候。迫切需要新的治疗方法。脑肽神经紧张素（NT）及其全活性衍生物NT[8-13]已被证明具有相当大的长期镇痛活性，然而这些化合物不能通过血脑屏障传递。在之前的努力中，我们设计了一种化合物ABS201，口服时具有显著的抗精神病潜力；最近，我们已经证明使用适当的大鼠神经性疼痛模型，它也有显著的镇痛活性。这些活性是通过化合物作为神经紧张素受体-(NTR-1)和NTR-2的激动剂的活性介导的。虽然ABS201作为一种镇痛药具有相当大的发展前景，但我们假设，进一步的合理设计将能够鉴定出一种衍生物，其中NTR-2/NTR-1受体的选择性可以增加，从而使抗精神病活性最小化或消除。具体目标将完成，以解决假设。在Specific Aim 1中，将合成一组10个ABS 201衍生物，旨在提高该化合物对NTR-2的选择性，从而保持镇痛活性。这些化合物（以及ABS201）将在Specific Aim 2中对3种大鼠模型的镇痛活性进行评估，并对慢性疼痛进行摇尾、热板和福尔马林试验。将对所有化合物进行IP和口服给药。在Specific Aim 3中，将评估其他潜在的鉴别因子，包括NTR-2和NTR-1的结合、血清稳定性和功能激动作用。根据这些研究的结果，将确定进入该项目的第二阶段的先导药物，这将包括进一步评估该化合物的功效、潜在毒性和适合提交IND的药代动力学特征。具体目标1将在Argolyn生物科学公司完成，而具体目标2和3将在南卡罗来纳医科大学的分包合同下完成。项目描述：慢性神经性疼痛是最重要的未满足的医疗需求之一。脑肽神经紧张素的一种口服活性衍生物已被确定，在大鼠中表现出相当于吗啡的有效镇痛活性，但具有独特的活性机制。该化合物具有作为一种新型慢性疼痛治疗剂的发展潜力。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Chronic, neuropathic pain is 1 of the most important unmet medical needs in the United States, affecting tens to hundreds of millions of people nationwide at some time during their lives. Novel therapeutic approaches are desperately needed. The brain peptides neurotensin (NT) and its fully active derivative NT[8-13] have been shown to exhibit considerable, long-term analgesic activity, however the compounds are unable to be delivered across the blood brain barrier. In previous efforts, we have engineered a compound, ABS201, that possesses significant antipsychotic potential when orally administered; recently, we have demonstrated using an appropriate rat model of neuropathic pain that it also has dramatic analgesic activity. These activities are mediated through the compound's activity as an agonist of neurotensin receptor-(NTR-1) and NTR-2, respectively. While ABS201 has considerable promise for development as an analgesic, we hypothesize that further rational design will enable identification of a derivative in which NTR-2/NTR-1 receptor selectivity can be increased such that the antipsychotic activity is minimized or eliminated. 3 Specific Aims will be completed to address the hypothesis. In Specific Aim 1, a set of 10 derivatives of ABS 201 will be synthesized that are designed to improve selectivity of the compound for NTR-2 over NTR-1 and thus retaining analgesic activity. These compounds (as well as ABS201) will be evaluated in Specific Aim 2 for analgesic activity in 3 rat models, the tail flick, hotplate and formalin assays for chronic pain. Both IP and oral dosing will be performed for all compounds. In Specific Aim 3, other potential discriminators, including NTR-2 and NTR-1 binding, serum stability and functional agonism will be evaluated. From the results of these studies, a lead will be identified for advancement into Phase 2 of this project, which will include further evaluation of the compound's efficacy, potential for toxicity and pharmacokinetic characterization appropriate for submission of an IND. Specific Aim 1 will be completed at Argolyn Bioscience while Specific Aims 2 and 3 will be completed under a subcontract at the Medical University of South Carolina. Project Narrative: Chronic, neuropathic pain is 1 of the most important unmet medical needs. An orally active derivative of the brain peptide neurotensin has been identified that exhibits potent analgesic activity in rats equivalent to morphine but with a unique mechanism of activity. This compound has the potential for development as a novel therapeutic agent for chronic pain.